Macaque monkeys are the most important animal model for AIDS vaccine development and are increasingly being used in biodefense research. An individual's immunogenetics can profoundly influence susceptibility to AIDS viruses and other pathogens. Indian-origin rhesus macaques have the most thoroughly characterized immunogenetics; however, their availability for research is extremely limited. Chinese-origin rhesus macaques, cynomolgus macaques, and pig-tailed macaques are increasingly relied upon to alleviate the shortage of Indian- rhesus macaques. As studies with these macaques become more common, there is a newfound appreciation that they may offer compelling advantages over Indian-origin rhesus macaques for specific studies. To study cellular immunity to AIDS viruses and biodefense, a comprehensive understanding of major histocompatibility complex (MHC) and killer immunoglobulin receptor (KIR) genetics is required. In the initial project period of this grant, MHC class I and II alleles were sequenced from cynomolgus macaques from different origins and the first MHC peptide binding motifs in cynomolgus macaques were determined. In this renewal, we will continue and expand this project by completing: Specific Aim 1, in which commonly expressed MHC class I and II alleles will be sequenced from cynomolgus, Chinese rhesus, and pig-tailed macaques. Specific Aim 2, in which full length KIR alleles will be sequenced from the same populations of macaques. Specific Aim 3, in which 8 MHC class I and 8 MHC class II peptide binding motifs will be determined. These Aims will take advantage of recent developments in high-throughput 'next generation' DNA sequencing to rapidly characterize full-length MHC and KIR alleles. At least 300 heretofore novel MHC class 1,150 MHC class II, and 300 KIR sequences will be identified. The experience of the investigative team in macaque immunogenetics, deep sequencing, and MHC biochemistry uniquely qualifies them to continue this important research. PUBLIC HEALTH RELEVANCE (provided by applicant): Macaque monkeys are widely used in the development and testing of prophylactic vaccines against AIDS viruses and pathogens with biodefense potential. Major histocompatibility complex (MHC) and killer immunoglobuline receptor (KIR) genetics influence susceptibility to these diseases. We will sequence novel alleles and define their functional attributes in macaque populations used for infectious disease research.